DE19539532A1 - Ophthalmic cromoglicate gel preparation - Google Patents

Abstract

The invention relates to an ophthalmic gel preparation comprising at least one cromoglycine derivative and at least one synthetic or natural polysaccharide, excluding cellulose derivatives, or gum as the gel-forming agent.

Description

The antiallergenic effect of cromoglicinic acid and its derivatives has been known for a long time. So finds cromolynic acid, also in grain combination with other pharmaceutical agents, their use and in other things in ophthalmology. A common dosage form exists in the form of aqueous solutions as eye drops, as they are For example, in EP 0 082 546 and EP 0 274 590 described who the.

A fundamental problem with the presentation in the form of eyes drop, is the low residence time of the drug in the eye.  

By leaking tear fluid, the drug can quickly out Washed out of the eye area and medically indicated te effective drug concentration at the site of action is quickly under reached.

Particularly problematic in the use of cromolyn sodium derivatives such as, preferably, disodium cromoglycate or its de rivaten (hereinafter referred to as "DNCG") is the by the Drug induced eye irritation, resulting in a strong "Eye burning" manifested. This is associated with a reinforced Secretion of tear fluid and involuntary inclination the patient to increased eye rubbing. Both lead to one Increased discharge of the active substance from the eye area. The Acceptance of DNCG-containing ophthalmic preparations is due the associated eye irritation in the patients ent speaking low.

There are several different proposals have become known as the necessary effective drug concentration of DNCG in the eyelid to be obtained over as long a period as possible.

Thus, the RD 199 024 describes an insert made of polymer material, that is placed between the eyelid and the eyeball and out which diffused out continuously DNCG. A disadvantage of this The procedure is that the patient considered the used Inlet as unpleasant perceive foreign bodies in the eye. In addition, this proposal very expensive.

LU 86 172 describes a DNCG methylcellulose composition, whose viscosity is large enough to not immediately get out of the Eye to be washed out and thus a sufficient dwell time of the drug in the eye area to effect. These gel formers must be used in relatively high concentration (2-3%) and then irritate the eye considerably. Another disadvantage is that  It often interferes with the use of methylcellulose Gluing the eyelid comes.

The above-described proposals also solve the problem of Eye irritation not.

U.S. Patent 4,136,173 describes an aqueous ophthalmic admixture Composition containing, inter alia, xanthan and locust bean rubber. The composition reversibly changes its physical Properties of liquid to gel depending on the pH Value. The liquid composition, which has a pH <5, can be dripped into the eyelid and goes into the gel Phase as soon as its pH value changes to the physiological pH Value in the eyelid has set. US 4 136 173 does not disclose the Use of cromoglicin as ophthalmic therapeutic, whether presumably she listwise considered active ingredients. With the eye irritant effects of DNCG is this prior art not concerned.

The object of the present invention is a dosage form for ophthalmic preparations containing at least one Cromoglicinderi vat provide as an active ingredient, the disadvantages described overcomes.

It has now surprisingly been found that Cromoglicinderivate, ins special DNCG in a gel based on xanthan or the like, natural or artificial gums not or only in ver strong reduced measure leads to eye irritation. Such gel preparations ver also avoid bonding problems, as with cellulose derivatives occur as a thickener.

The present invention solves the problem ophthalmic gel preparation ready to base an active ingredient of cromoglicic acid or its derivatives, an artificial or  natural gum, preferably xanthan gelling agent and optionally other ophthalmic preparations contain conventional additives. The ophthalmic gel is preferably prepared by adding a gum, in particular xanthan solution is prepared and to this a Lö solution containing at least one Cromoglicinderivat added and mixed in. Furthermore, active ingredients or conventional Zu for the preparation of ophthalmic preparations, such as in particular cetrimide, sorbitol and EDTA are added. The Solution is then cleaned of residues as far as necessary, for Example by filtration, and then possibly homogenized and sterilized.

The advantageous properties according to the invention are in particular dere achieved by the fact that the gel preparation an artificial or natural gum, preferably xanthan gum.

As "xanthan" are the exocellular biopolysaccharides be records which of the microorganism Xanthomonas Campestres be formed.

Particularly preferred as active ingredient is DNCG, the (double) Na triumsalz of cromolyn sodium.

In addition, the preparation may also contain other active ingredients or Wirk fabric combinations, as well as gelling agents, solution aids, upper surface-active substances, complexing agents, disinfectants or pH adjusting agents included. The listing of the addition substances is only an example and not exhaustive; all in the Preparation of ophthalmic preparations usual additives will be considered. The choice of additives is off depending on the desired properties and the intended use of the Preparation and can be made easily by a person skilled in the art.

As a solvent, the gel preparation preferably contains water.  

The preparation of the preparation is done in a preferred Embodiment according to the following description. All information are in grams or percent by weight:

• - By dissolving xanthan in water is about 1.5% Gum solution (mucus) produced.
• Furthermore, an aqueous active substance salt solution is prepared, about 4.4% cromolyn sodium, about 7.6% sorbitol, 0.02% Ce trimid and 0.02% EDTA.
• - The pH is adjusted to about 6 with 0.1 N NaOH.
• - The salt solution is purified by filtration of residues.
• - Then the solutions are combined in equal volumes and homogenized.
• - The combined solution is autoclaved, if necessary, is evaporated Solvent added.

This description of the preparation of the preparation is natural only as an example and not restrictive. Depending on the desired properties and intended uses of the preparation, can by the skilled person, familiar to him, the Together tion of the preparation or the production process changed who the. This applies, for example, changing, omitting, adding gene or merge individual production steps or a Change their order.

The same applies to the following embodiments:

Example 1 Composition of the ophthalmic preparation

Xanthan | 13.0 g sorbitol 38.0 g Cromoglicic acid, disodium salt 20.0 g Na Edeteat 0.1 g cetrimide 0.1 g water 927.13 g 1N NaOH for pH adjustment

Production of the ophthalmic preparation

• - In about 500 g of water, the xanthan gum is dissolved
• - in the residual amount of water, cromolyneclic acid, Cetrimide, sorbitol and EDTA dissolved
• - The salt solution is over a 0.2 microns Cellulose acetate filter filtered (unsterile conditions)
• - After the salt solution and the xanthan (gel) are combined and homogenized; if necessary, the pH is adjusted to 6.0 with 1N NaOH provides
• - In a glass bottle, the entire approach over 20 minutes at Autoclaved at 121 ° C; the amount of water by autoclaving evaporated, is supplemented.

This is followed by filling the preparation into sterile 10 g polyfoil tubes.

example 2 Composition of the ophthalmic preparation

Xanthan | 9.0 g   Cromoglicic acid, disodium salt 20.0 g cetrimide 0.1 g sorbitol 38.0 g Na Edeteat 0.1 g 1N NaOH for pH adjustment @ water 931.13 g

Production of the ophthalmic preparation

• - In about 500 g of water, the xanthan gum is dissolved
• - in the residual amount of water are successively cromoglicinic acid, Cetrimide, sorbitol and EDTA dissolved
• - The salt solution is over a 0.2 microns Cellulose acetate filter (Sartorius) filtered (unsterile conditions gene)
• - After the salt solution and the xanthan (gel) are combined and homogenized; the pH may be adjusted to 6.0 with IN NaOH provides
• - In a glass bottle, the entire approach over 20 minutes at Autoclaved at 121 ° C; the amount of water by autoclaving evaporated, is supplemented.

This is followed by filling the preparation into sterile 10 g polyfoil tubes.

The preparations according to Examples 1 and 2 show no in the test significant eye irritation. Gluing etc. were not be obachtet. The residence time and constant concentration of the active substance at the eye corresponds to the therapeutic needs. The gel The preparation is well accepted by the test persons.

Claims (7)

1. Ophthalmic gel preparation containing at least one Cromoglicinderivat, characterized in that the gel preparation contains at least one artificial or natural polysaccharide or natural rubber as gelling agent. 2. Preparation according to claim 1, characterized, that the polysaccharide or gum xanthan or a xanthan derivative is.   3. A preparation according to claim 2, characterized, that the concentration of gum, especially xanthan gum from 0.1 to 5 weight percent, preferably from 0.5 to 2.5 particularly preferably 0.7-1.5 weight percent based on the Total amount of the preparation is. 4. Preparation according to one of the preceding claims, characterized, at least one further active ingredient (eg xylomethazoline) or an active ingredient combination is contained in the preparation. 5. Preparation according to one of the preceding claims, characterized, that the preparation further gel-forming, stabilizing, des infecting, surface-active or complexing sub punching, or combinations thereof. 6. Preparation according to one of the preceding claims, characterized, that the preparation has a pH of 4-7, preferably from about 6 has. 7. Ophthalmic gel preparation having the following composition:
xanthan gum
0.1-5 wt.%, Preferably 0.7-1.5 wt.%
Disodium cromoglycate
0.5-5% by weight, preferably about 2% by weight
sorbitol
1-7% by weight, preferably 3-4.5% by weight
cetrimide
0.001-0.1% by weight, preferably 0.008-0.02% by weight
Na Edeteat
0.001-0.1% by weight, preferably 0.008-0.02% by weight
NaOH solution for pH adjustment to 4-7, preferably to about 6
Balance solvent, preferably water